Assessing DNA polymerase theta as a therapeutic target in BRCA1 mutant cancer
评估 DNA 聚合酶 θ 作为 BRCA1 突变癌症的治疗靶点
基本信息
- 批准号:10579323
- 负责人:
- 金额:$ 42.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-01 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:AllelesBRCA mutationsBRCA1 MutationBRCA1 ProteinBRCA1 geneBRCA2 MutationBiological AssayBiological FactorsBiological MarkersBreastCancer PatientCancer cell lineCell LineCellsCessation of lifeChromosome PairingClinicalClinical ResearchCollaborationsDNADNA RepairDNA Repair PathwayDNA biosynthesisDNA sequencingDNA-Directed DNA PolymeraseDataDependenceDrug resistanceEventExcisionFutureGeneticGoalsHumanImmunofluorescence MicroscopyIn VitroKnock-outKnockout MiceKnowledgeMalignant NeoplasmsMalignant neoplasm of ovaryMeasuresMediatingMolecularMutateNamesOutcomePatientsPoly(ADP-ribose) Polymerase InhibitorPoly(ADP-ribose) PolymerasesPolymeraseProcessProteinsPublishingReporterResistanceRoleSingle-Stranded DNASiteTestingUnited StatesWorkcancer therapycell typeclinical applicationhomologous recombinationin vivoinhibitorinhibitor therapyinsightmalignant breast neoplasmmutantnucleasepatient derived xenograft modelpatient populationpatient stratificationpharmacologicpreclinical developmentrefractory cancerrepairedsmall moleculesmall molecule inhibitortherapeutic targettherapeutically effectivetherapy developmenttreatment strategy
项目摘要
PROJECT SUMMARY
Genetic disruption of DNA polymerase theta (Polθ) activity has been shown to effectively target BRCA1 mutated
cells, while leaving BRCA1 wild-type (WT) cells intact. Polθ facilitates theta-mediated DNA end joining (TMEJ)
repair by promoting DNA synapsis and repair synthesis at break sites containing 3' single stranded (ss)DNA
overhangs. Although small molecule inhibitors of Polθ activity are currently under development for the treatment
of BRCA1 mutant cancers, very little is known regarding the mechanisms that activate TMEJ and result in Polθ-
dependency in BRCA1 mutant cells. Moreover, the current paradigm assumes that homologous recombination
(HR)-deficiency confers Polθi sensitivity, therefore PARPi responsiveness is expected to be a biomarker for Polθ
inhibitor (Polθi) sensitivity. In our preliminary data, we unexpectedly identified commonly used Brca1 mutant
cells that grow relatively unperturbed with genetic Polq (Polθ) knockout (KO), indicating that Polθi and PARPi
sensitivity may not necessarily correlate. In this proposal, we will elucidate the molecular requirements for TMEJ
activation and identify biological factors that distinguish PARPi and Polθi sensitivity. We will address the following
Specific Aims: 1) reveal the molecular basis of TMEJ activation in Brca1 mutant cells; 2) uncover genetic Polθ-
dependencies in Brca1 mutant cells; and 3) examine pharmacologic Polθ inhibition in Brca1 mutant cells.
Collectively, these studies will be informative for future clinical studies employing Polθi.
项目摘要
DNA聚合酶θ(Polθ)活性的遗传破坏已被证明可有效靶向突变的BRCA 1。
细胞,而使BRCA 1野生型(WT)细胞保持完整。Polθ促进θ介导的DNA末端连接(TMEJ)
通过促进DNA突触的修复和在含有3'单链(ss)DNA的断裂位点的修复合成
悬垂部分。尽管目前正在开发Polθ活性的小分子抑制剂用于治疗
在BRCA 1突变型癌症中,关于激活TMEJ并导致Polθ-的机制知之甚少。
BRCA 1突变细胞的依赖性。此外,目前的范式假设同源重组,
(HR)缺乏导致Polθi敏感性,因此PARPi反应性预期是Polθ的生物标志物
抑制剂(Polθi)敏感性。在我们的初步数据中,我们意外地发现了常用的Brca 1突变体,
在基因Polq(Polθ)敲除(KO)的情况下,细胞生长相对不受干扰,表明Polθi和PARPi
灵敏度可能不一定相关。在这个建议中,我们将阐明TMEJ的分子要求
激活和识别区分PARPi和Polθi敏感性的生物因子。我们将解决以下问题
具体目的:1)揭示Brca 1突变细胞中TMEJ激活的分子基础; 2)揭示遗传Polθ-
Brca 1突变细胞中的依赖性;和3)检查Brca 1突变细胞中的药理学Polθ抑制作用。
总之,这些研究将为未来使用Polθi的临床研究提供信息。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Neil Johnson其他文献
Neil Johnson的其他文献
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{{ truncateString('Neil Johnson', 18)}}的其他基金
Assessing DNA polymerase theta as a therapeutic target in BRCA1 mutant cancer
评估 DNA 聚合酶 θ 作为 BRCA1 突变癌症的治疗靶点
- 批准号:
10446399 - 财政年份:2022
- 资助金额:
$ 42.14万 - 项目类别:
Assessing DNA Polymerase Theta as a Therapeutic Target in BRCA1 Mutant Cancer
评估 DNA 聚合酶 Theta 作为 BRCA1 突变癌症的治疗靶点
- 批准号:
10884036 - 财政年份:2022
- 资助金额:
$ 42.14万 - 项目类别:
Dissecting BRCA1-PALB2 Activity in DNA Repair and Development
剖析 BRCA1-PALB2 在 DNA 修复和发育中的活性
- 批准号:
10664883 - 财政年份:2020
- 资助金额:
$ 42.14万 - 项目类别:
Dissecting BRCA1-PALB2 Activity in DNA Repair and Development
剖析 BRCA1-PALB2 在 DNA 修复和发育中的活性
- 批准号:
10229611 - 财政年份:2020
- 资助金额:
$ 42.14万 - 项目类别:
Dissecting BRCA1-PALB2 Activity in DNA Repair and Development
剖析 BRCA1-PALB2 在 DNA 修复和发育中的活性
- 批准号:
10453625 - 财政年份:2020
- 资助金额:
$ 42.14万 - 项目类别:
The role of microhomology-mediated end joining in Fanconi anemia pathogenesis
微同源介导的末端连接在范可尼贫血发病机制中的作用
- 批准号:
10580006 - 财政年份:2020
- 资助金额:
$ 42.14万 - 项目类别:
Dissecting BRCA1-PALB2 Activity in DNA Repair and Development
剖析 BRCA1-PALB2 在 DNA 修复和发育中的活性
- 批准号:
10388570 - 财政年份:2020
- 资助金额:
$ 42.14万 - 项目类别:
The role of microhomology-mediated end joining in Fanconi anemia pathogenesis
微同源介导的末端连接在范可尼贫血发病机制中的作用
- 批准号:
10367981 - 财政年份:2020
- 资助金额:
$ 42.14万 - 项目类别:
Compensatory mechanisms that promote homologous recombination in BRCA1 mutant cancers
促进 BRCA1 突变癌症同源重组的补偿机制
- 批准号:
10242152 - 财政年份:2019
- 资助金额:
$ 42.14万 - 项目类别:
Compensatory mechanisms that promote homologous recombination in BRCA1 mutant cancers
促进 BRCA1 突变癌症同源重组的补偿机制
- 批准号:
9762056 - 财政年份:2019
- 资助金额:
$ 42.14万 - 项目类别:
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